Summary Pancreatic ductal adenocarcinoma (PDA) is the 5th leading cancer diagnosis in the USA and is highly lethal. There are no effective means to prevent or delay PDA onset and few effective treatment options exist once transformation has occurred. Bacterial dysbiosis is emerging as an accomplice to carcinogenesis in extra- pancreatic malignancies such as colon and liver cancer. Nevertheless, the gut microbiome has not been clearly implicated in carcinomas remote from the intestinal lumen or its drainage. There are tangential data, however, that support an association between PDA and gut bacteria. For example, the oral microbiome in patients with PDA has been found to substantially differ from control subjects. Further, our laboratories have obtained critical preliminary data which suggest that the intestinal microbiome may be an important regulator of PDA development in genetically predisposed hosts: (i) We found that intraluminal gut bacteria can directly access the pancreas; (ii) The relative abundance of select bacterial taxa was higher in the gut of PDA patients compared with healthy individuals; (iii) Specific pattern recognition receptors (PRRs), which transduce inflammation in response to microbial pathogens, are highly expressed in the PDA tumor microenvironment (TME) and activation of these receptors accelerates tumorigenesis whereas mice deficient in select PRRs have slower progression of PDA; (iv) Endo-luminal administration of pathogenic bacteria accelerates tumorigenesis in genetically predisposed mice whereas germ-free mice are protected from PDA. (v) Select bacterial byproducts induce recruitment of regulatory T cells, M2-polarized macrophages, and myeloid derived suppressor cells to the PDA TME. Based on these data, we postulate that pathogenic gut bacteria drive pancreatic oncogenesis in at-risk hosts via activation of specific PRRs which leads to pathogen-induced immune suppression. In Aim 1 we will define the gut and intra-pancreatic microbiome in mice developing PDA compared with WT mice, we will contrast the microbial phenotypes associated with aggressive PDA compared with slowly progressive cancer in genotypically identical hosts, and determine whether humans with PDA harbor a distinct gut and pancreatic microbiome compared with age-matched control patients. In Aim 2, we will test our hypothesis that gut microbes influence oncogenesis by examining whether directly modulating the microbiome alters the rate of tumor progression. As such, we will identify the specific endoluminal bacteria which affect the progression of pancreatic oncogenesis. In Aim 3, we will test our hypothesis that select luminal pathogens promote pancreatic tumorigenesis by inducing immune suppression via ligation of select Toll-like receptors and NOD-like receptors. Our experiments will provide critical new information on the mechanism of pancreatic oncogenesis. We will also identify novel risk factors and provide guidance for the development of innovative therapeutics aimed at PDA prevention in at-risk hosts.